The circulatory system in humans and other vertebrate animals includes a heart, which pumps blood throughout the body, and a vascular system, which is a series of tubes supplying blood to all regions of the body. The blood leaves the heart through arteries, which transport the blood under high pressure to the tissues of the body. Blood returns to the heart from the tissues through veins. The arteries repeatedly subdivide into progressively thinner tubes and eventually give rise to arterioles. The arterioles feed into capillaries, which are thin walled structures through which oxygen exchange occurs within tissues. Blood from the capillaries then enters small venous structures called venules, which merge repeatedly to form veins, which carry the blood back to the heart. Collectively, the arterioles, capillaries, and venules are referred to as the “microvasculature”.
The arterioles, unlike the other portions of the microvasculature, have smooth muscle fibers in their walls. These fibers regulate blood flow into and through the microvasculature by contracting and dilating as needed. In this way, the arterioles control the distribution of blood in the body and maintain systemic blood volume and arterial blood pressure within physiologic limits.
Shock is a progressive, widespread reduction in tissue perfusion that results from a decrease in effective circulating blood volume causing a decrease in oxygen delivery and exchange within capillaries. If untreated, shock is often fatal.
Shock may be due to several causes, which has led to the classification of shock into several categories. Thus, shock due to loss of blood volume due, for example, to hemorrhage or to microvascular blood pooling, is termed hypovolemic shock. Shock due to failure of the heart to adequately pump blood throughout the body is termed cardiogenic shock. Shock has also been classified as being vasogenic, that is due to a maldistribution of blood to the tissues, such as due to acute vasodilation without a concomitant increase in intravascular volume, resulting in inadequate tissue perfusion. Vasogenic shock is seen with shock due to sepsis, anaphylaxis, and neurogenic injury. Regardless of the cause of shock, however, if untreated shock can lead to severe complications including myocardial depression, acute respiratory distress, renal failure, disseminated intravascular coagulation, and death.
Shock is treated by diagnosing and correcting, if possible, the underlying cause of the shock, such as by controlling bleeding or re-starting the heart, treating the effects of shock, such as administering oxygen and correcting acid-base imbalance, and by supporting vital functions, such as by administering fluids to maintain blood pressure and heart function. Medications that are useful in combating shock include inotropic drugs to increase the strength of cardiac contraction, corticosteroids which stabilize membranes, vasopressors which cause constriction of blood vessels and thus help to maintain arterial blood pressure, and narcotics to relieve pain and anxiety associated with shock.
However even with such treatment, severe shock, due to any or a combination of causes, may progress and result in permanent complications or death. Thus, there is an ongoing need to develop new and additional methods for treating and for preventing shock.
Cannabinoids are a class of chemical compounds that are naturally produced in plants and in animals. Plant produced cannabinoids include Δ9-tetrahydrocannabinol (THC) and Δ8-tetrahydrocannabinol, the first of which is the psychotropic principle in marijuana. Cannabinoids that are endogenously produced in animals are referred to as endocannabinoids, and include arachidonyl ethanolamide (anandamide) and 2-arachidonyl glycerol (2-AG). Additionally, there are a large number of synthetic cannabinoid analogs, including synhexyl, nabilone, and non-classical cannabinoids, such as CP55940, aminoalkylindole (WIN 55212), and diarylpyrazoles.
Kunos, et al., U.S. Pat. No. 5,939,429, incorporated herein by reference, discloses that cannabinoids may be useful in treating hemodynamic abnormalities such as hypotension or hypertension. As disclosed in Kunos, administration of a cannabinoid receptor agonist, such as anandamide, causes hypotension. Conversely, administration of a cannabinoid receptor antagonist, such as SR141716A, prevents anandamide-induced hypotension. Thus, Kunos concluded that the use of a drug that selectively blocks cannabinoid receptors will be of therapeutic value by preventing or attenuating endotoxin-induced hypotension. Additionally, because agonists of cannabinoid receptors lower blood pressure, Kunos concluded that such agents could be used to treat conditions associated with excessive vasoconstriction, such as hypertension, peripheral vascular disease, or angina pectoris.
The hypotensive effect of cannabinoids has been reported widely in the scientific literature. Each of the following scientific references is incorporated herein by reference and discloses that cannabinoids cause hypotension when administered to animals. (1) Kunos, G., et al., Prostaglandins & other Lipid Mediators, 61:71-84 (2000); (2) Lake, K D, et al., Journal of Pharmacology and Experimental Therapeutics, 281(3):1030-1037 (1997); (3) Hilliard, C J, Journal of Pharmacology and Experimental Therapeutics, 294(1):27-32 (2000); (4) Brown, D J, et al., Journal of Pharmacology and Experimental Therapeutics, 188(3):624-629 (1974); (5) Adams, M D, Journal of Pharmacology and Experimental Therapeutics, 196(3):649-656 (1976); (6) Kunos, G, et al., Chemistry and Physics of Lipids, 108:159-168 (2000); (7) Wagner, J A, et al., Journal of Molecular Medicine, 76:824-836 (1998); (8) Siqueira, S W, et al., European Journal of Pharmacology, 58:351-357 (1979); and (9) Wagner, J A, et al., Nature, 390:518-521 (1997). Adams, reference (5) above, discloses that, although intravenously administered Δ9-tetrahydrocannabinol or Δ8-tetrahydrocannabinol caused decreases in blood pressure, intra-arterially administered Δ9-tetrahydrocannabinol or Δ8-tetrahydrocannabinol produced an increase in blood pressure indicative of vasoconstriction. When administered intravenously, Adams reports that THC produced a transient increase in blood pressure that lasted only about one minute and that was followed by a more prolonged hypotensive response. Wagner, reference (8) above, discloses that administration of the cannabinoid THC or HU-210 doubled survival time from about 30 minutes to 60 minutes in rats that were subsequently bled. Wagner states that the mechanism for this improvement in survival is unclear and speculates that it may be due to a favorable redistribution of cardiac output or improved microcirculation by localized vasodilation.
Kunos, U.S. Pat. No. 5,939,429, further suggests that activation of cannabinoid receptors may be beneficial for survival in hemorrhagic shock, probably because the hypotension caused by the cannabinoid agonist counters the excessive compensatory hypertension that occurs following hemorrhage. It is because of this vasodilatory effect that cannabinoid receptor agonists are suggested to be useful in the treatment of hemorrhagic shock and other conditions associated with excessive vasoconstriction, such as hypertension, peripheral vascular disease, and certain forms of angina pectoris.
Information on the blood pressure effects of COX-2 inhibitors is inconclusive. Johnson, D L, The Annals of Pharmacotherapy, 37:442-446 (March 2003) reported on several studies of the effects of COX-2 inhibitors on blood pressure and on reports of elevated blood pressure as an adverse effect of COX-2 inhibitors. Johnson discloses that were inconclusive. Short-term trials suggested that COX-2 inhibitors have no effect on blood pressure on normotensive patients, although these studies may have been flawed because the study subjects were restricted to a low-sodium diet. In another study in which patients were administered either rofecoxib or celecoxib for six weeks, rofecoxib was found to elevate blood pressure and the results on celecoxib were inconclusive. Johnson also reported that some limited data suggests that blood pressure may increase following initiation of therapy with COX-2 inhibitors. Johnson concluded by stated that despite the information provided, it is currently unknown whether an association exists between COX-2 inhibitor therapy and blood pressure elevations. Johnson did not disclose or suggest any effect of COX-2 inhibitors on arterial microvasculature.
Dilger K., et al., Journal of Clinical Pharmacology, 42:985-994 (2002) evaluated the effects of celecoxib, a specific COX-2 inhibitor, and diclofenac, a non-specific COX inhibitor, on blood pressure, renal function, and vasoactive prostanoids in both young and elderly patients. Dilger concluded that their study provided evidence that therapeutic doses of either celecoxib or diclofenac given for 15 days are apparently not associated with significant changes in blood pressure or renal function in healthy young or elderly subjects. Dilger did not disclose or suggest any effect of COX inhibitors on arterial microvasculature.
To date, other than the Adams reference (5) described above which discloses intra-arterial administration of THC, there have been no published reports on the use of either a cannabinoid receptor agonist or a COX-2 inhibitor to cause constriction of arterial microvasculature.